JP2008155014A - Medical material for obstructing accretion - Google Patents
Medical material for obstructing accretion Download PDFInfo
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- JP2008155014A JP2008155014A JP2007308635A JP2007308635A JP2008155014A JP 2008155014 A JP2008155014 A JP 2008155014A JP 2007308635 A JP2007308635 A JP 2007308635A JP 2007308635 A JP2007308635 A JP 2007308635A JP 2008155014 A JP2008155014 A JP 2008155014A
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Abstract
Description
本発明は、創傷部とその周囲組織との間に生じる癒着を阻止する医用材料に関し、より詳しくは、本発明は生体内親和性基材からなる構造物として、生体内親和性基材として生体内非吸収性物質を用いた場合には、癒着を阻止した後に生体の構造物として機能させることができ、また生体内親和性基材として生体内分解吸収性物質を用いた場合には、生体内に植え込まれると、癒着防止を達成できるまでの一定期間経過後に分散し分解吸収される癒着阻止用医用材料に関する。 The present invention relates to a medical material that prevents adhesion occurring between a wound part and its surrounding tissue. More specifically, the present invention relates to a structure composed of an in vivo compatible base material and a biocompatible base material. When a non-absorbable substance in the body is used, it can function as a biological structure after blocking adhesion, and when a biodegradable absorbable substance is used as a biocompatible substrate, The present invention relates to an adhesion-preventing medical material that, when implanted in the body, is dispersed and decomposed and absorbed after a lapse of a certain period until the prevention of adhesion can be achieved.
癒着阻止用医用材料には、現在臨床では主としてGenzyme Corporationが製造する癒着防止材料が使用されている。これはヒアルロン酸とカルボキシメチルセルロース（CＭC）を脱水剤であるカルボジイミドを用いて架橋を導入したポリアニオン系の親水性生分解性ポリマーからなり、SeprafilmTRの名で発売されている。本製品は腹部手術での癒着防止を目的とした製品である。しかし本製品は胸部外科領域での癒着防止は製品の適応外であり、実際動物実験で胸部外科領域に用いても効果は見られない。しかし、なぜ腹部で効果を発揮し、胸部では効果がないのかは明らかにされていない。 Anti-adhesion materials produced mainly by Genzyme Corporation are currently used in clinical practice as anti-adhesion medical materials. This is a polyanionic hydrophilic biodegradable polymer in which hyaluronic acid and carboxymethylcellulose (CMC) are crosslinked using carbodiimide, which is a dehydrating agent, and is sold under the name Seprafilm TR . This product is designed to prevent adhesions during abdominal surgery. However, this product is not suitable for prevention of adhesions in the field of thoracic surgery and is not effective even when used in thoracic surgery in actual animal experiments. However, it is not clear why it is effective in the abdomen and ineffective in the chest.
従来の癒着予防に関する技術としては、大きく３に分けられると考えられる。一つは癒着予防が必要な部位に、物理的障壁として挿入し癒着を予防する（非特許文献、および特許文献１〜３）、二つ目はその材料自身に細胞を排除する性質を持たせることで、癒着を予防するもので、細胞を排除するための形状面での工夫も行われている（特許文献４〜６）。最後はその材料から癒着を予防し得る物質を放出することで、その周囲の癒着を予防するものである（特許文献７，８）。
非特許文献１にはシリコーンを用いた癒着防止が述べられている。
特許文献１にはPTFEを用いた透明性の高い癒着防止材料が開示されている。
特許文献２にはセルロース誘導体を原料とした癒着防止材料が開示されている。
特許文献３には生体内分解性ポリマーである乳酸とグリコール酸からなる癒着防止材料が開示されている。
特許文献４には親水性ポリマーによる被覆によって、癒着を予防する手段が開示されている。
特許文献５にはポリイオンコンプレックスからなる癒着防止材料が開示されている。
特許文献６には生体内分解性ポリマーの繊維構造体による癒着防止材料が開示されており、繊維の太さ、窪みのサイズが規定されている。
特許文献７にはヘパリンが含有された癒着防止バリアーが開示されている。
特許文献８にはTIMP1に対する抗体あるいはアンチセンスによる癒着防止方法が開示されている。
特許文献９にはヒアルロン酸の如き、ポリアニオン系ポリマーのハイドロジェルで癒着が阻止できると記載されている。
Non-Patent Document 1 describes prevention of adhesion using silicone.
Patent Document 1 discloses a highly transparent anti-adhesion material using PTFE.
Patent Document 2 discloses an adhesion preventing material using a cellulose derivative as a raw material.
Patent Document 3 discloses an adhesion preventing material composed of lactic acid and glycolic acid which are biodegradable polymers.
Patent Document 4 discloses a means for preventing adhesion by coating with a hydrophilic polymer.
Patent Document 5 discloses an adhesion preventing material composed of a polyion complex.
Patent Document 6 discloses an anti-adhesion material using a biodegradable polymer fiber structure, in which the thickness of the fiber and the size of the recess are defined.
Patent Document 7 discloses an adhesion preventing barrier containing heparin.
Patent Document 8 discloses an adhesion prevention method using an antibody or antisense to TIMP1.
Patent Document 9 describes that adhesion can be prevented with a hydrogel of a polyanionic polymer such as hyaluronic acid.
しかし、例えばシリコーン膜を癒着予防が必要な臓器あるいは組織の間に置くことで癒着組織形成を阻止できる場合もあるが、いかなる部位でも癒着阻止が達成できず、さらに創傷部位と周囲組織間を隔てるために置くための材料自体が問題となる場合があった。例えばシリコーン膜を使用した場合には、それを取り囲んで被包組織が形成され、その被包組織よる癒着や瘢痕性の収縮などの障害が生じていた。
その様な問題を克服するために、生体内で吸収可能な物質による癒着防止が計られるようになった。生体内で吸収される生分解性の医用材料は、縫合糸を始め、多くの領域で使用されてきており、その多くは生体内に植え込まれた後に3ケ月程度で、例えば縫合糸の場合では力学的強度が低下し、かなりの部分が劣化して吸収が開始されるなどの特性を持つ。現在、臨床の場ではポリ乳酸やポリグリコール酸、ポリカプロン酸などが使用され、メッシュ状や膜状の材料として使用されている実績のある材料ではあるが、これらの多くの材料は疎水的な性質を持つ材料であって、材料自体の生体との親和性に問題が残っている。
However, in some cases, for example, a silicone membrane may be placed between organs or tissues that require adhesion prevention, but adhesion formation cannot be achieved at any site, and the wound site and surrounding tissue are separated. In some cases, the material for placing the material becomes a problem. For example, when a silicone membrane is used, encapsulated tissue is formed surrounding the silicone membrane, and problems such as adhesion and scarring contraction due to the encapsulated tissue have occurred.
In order to overcome such problems, it has become possible to prevent adhesion by substances that can be absorbed in vivo. Biodegradable medical materials absorbed in vivo have been used in many areas, including sutures, many of which are about three months after being implanted in the body, for example, in the case of sutures Then, the mechanical strength is lowered, and a significant portion is deteriorated and absorption is started. Currently, polylactic acid, polyglycolic acid, polycaproic acid, etc. are used in clinical settings, and these are materials that have been used as mesh or membrane materials, but many of these materials are hydrophobic. There remains a problem in the affinity of the material itself with the living body.
生分解性物質のうち、親水性ポリマーで生分解性の特性が利用されているが、これらのポリマーを用いたin vitroのテストでは、48時間までの間は、細胞の侵入が阻止されていることが示されているが、それ以降は細胞が侵入しており、癒着の阻止は困難と考えられる。
これら生体内非吸収性または生体内吸収性物質による癒着防止は、材料自身によって創傷部と周囲組織の接触を遮断することで癒着を防止することを基本としている。しかし、この方法では完全に細胞の侵入を抑えることが難しく、確実な癒着阻止を達成することは困難、あるいは材料自身の問題が課題として残っている。
またポリアニオン系ポリマーのハイドロジェルによる癒着防止も知られているが、ハイドロジェルの形態維持性の低さが問題となり、圧迫などに抗して確実に創傷部と周囲組織の接触を予防する能力は低い。
Among biodegradable substances, biodegradable properties are used in hydrophilic polymers, but in vitro tests using these polymers prevent cell entry for up to 48 hours After that, cells have invaded and it seems difficult to prevent adhesions.
The adhesion prevention by these non-bioabsorbable or bioabsorbable substances is based on preventing adhesion by blocking contact between the wound part and surrounding tissue by the material itself. However, with this method, it is difficult to completely suppress the invasion of cells, it is difficult to achieve reliable adhesion prevention, or the problem of the material itself remains as a problem.
In addition, polyanion polymer hydrogels are also known to prevent adhesion, but low hydrogel shape maintenance is a problem, and the ability to reliably prevent contact between wounds and surrounding tissues against pressure, etc. Low.
一方、癒着防止材料より癒着を予防する物質、具体的にはヘパリンを用いた癒着防止も試みられている。ヘパリンを用いることによってフィブリン網の形成が阻害されるため、遊走細胞は足場であるフィブリン網が無いために、癒着が形成されないとの仮定に基づくものである。しかしながら、この方法の欠点として、ヘパリンを徐放出させ続けねばならない事にある。そのために手術後にヘパリンによる副作用のため出血が生じる恐れから使用に制限があり、出血をそれほど気にしない部位、もしくはその様な手術にしか使用できない問題があった。さらには癒着防止の効果を十分に得ることができなかった。 On the other hand, attempts have been made to prevent adhesion using a substance that prevents adhesion, specifically, heparin, from the adhesion preventing material. Since the formation of the fibrin network is inhibited by using heparin, the migratory cells are based on the assumption that no adhesion is formed because there is no fibrin network as a scaffold. However, a disadvantage of this method is that heparin must be released slowly. For this reason, there is a problem that it can be used only in such a region where the bleeding is caused by a side effect due to heparin after surgery and the bleeding is likely to occur, or the site where the bleeding is not much concerned. Furthermore, the effect of preventing adhesion could not be obtained sufficiently.
原料物質としての課題の他に、その効果について癒着阻止が困難な部位、組織等で重大な課題がある。
従来の癒着防止材料では癒着防止効果、特に腹腔内の手術で癒着防止効果が見られる場合がある。たとえば、小腸漿膜表面の傷であれば、癒着組織が形成される前段階として傷の上にフィブリンのネットワークが形成される。そしてそのネットワークが周囲の腸管もしくは腹腔壁との間を結びつけて、そこに線維芽細胞が侵入し、コラーゲン線維を産生して癒着組織を作り始める。この現象は、3日から始まり7日程度で極めて活発となる。
しかしながら多くの腹腔内での手術、小腸の手術の後では、術後2ないし3日目には腸管の蠕動運動が始まる。そうなると、腸管が大きく動くので、その力によって、創傷部と周囲組織との間に形成されたフィブリンのネットワークは容易にちぎられて、周囲組織との間の結合が剥がれ、その結果、その部位での癒着組織の形成にまでは至らない。術後2ないし3日目には、線維素溶解現象によってフィブリンのネットワークが溶かされるので、フィブリン網は弱くなり、ちぎれやすくなっている。つまり、組織に活発な動きがある場合には、その動きのために癒着のきっかけとなるフィブリン網が壊されるため、癒着が形成されず、使用した癒着防止材料による効果とは言い難い。
In addition to the problem as a raw material, there are serious problems regarding the effect, such as in sites and tissues where adhesion prevention is difficult.
Conventional anti-adhesion materials may have an anti-adhesion effect, particularly an anti-adhesion effect in intraperitoneal surgery. For example, in the case of a wound on the surface of the serous membrane of the small intestine, a fibrin network is formed on the wound as a stage before the adhesion tissue is formed. The network connects the surrounding intestinal tract or abdominal wall, and fibroblasts invade it, producing collagen fibers and starting to form adhesions. This phenomenon starts on the 3rd and becomes extremely active on the 7th.
However, after many intraperitoneal and small intestine operations, peristaltic movement of the intestinal tract begins 2 to 3 days after the operation. Then, the intestinal tract moves so much that the force easily breaks the network of fibrin formed between the wound and the surrounding tissue, causing the bond between the surrounding tissue to break and, as a result, at that site. It does not lead to the formation of adhesion tissues. On the second or third day after the operation, the fibrin network is dissolved by the fibrinolysis phenomenon, so the fibrin network becomes weak and easily broken. That is, when there is an active movement in the tissue, the fibrin network that triggers the adhesion is broken due to the movement, so that no adhesion is formed, and it is difficult to say that the effect of the used anti-adhesion material.
腹腔内で自由に動く小腸の影響があるところではそのような現象が期待され、癒着は生じにくい。しかしながら、骨盤内の傷や、大腸の後腹膜に固定された領域に近いあたりの傷、腹腔内の大網組織が傷の全面に位置した場合等では、腸管の自由な動きによる癒着組織形成の自然な阻止作用が及ばないので、癒着を生じやすい。
また腹腔内にある大網組織では、腸管のような大きな蠕動運動がないので形成されたフィブリン網がちぎれるような動きが期待できないことから、癒着は発生しやすい。
Such a phenomenon is expected where there is an influence of the small intestine that moves freely in the abdominal cavity, and adhesion is unlikely to occur. However, if the wound in the pelvis, the wound near the area fixed to the retroperitoneum of the large intestine, or the omentum tissue in the abdominal cavity is located on the entire surface of the wound, adhesion tissue formation due to free movement of the intestinal tract Since it does not have a natural inhibitory effect, it tends to cause adhesions.
In addition, in the omentum tissue in the abdominal cavity, since there is no large peristaltic movement like the intestinal tract, it is not possible to expect a movement that tears the formed fibrin network, so adhesion is likely to occur.
更には胸腔内や頭蓋内、心膜内、硬膜内などにおいては、術後2ないし3日後に始まる腸管の大きな動きというのは無いのでその部位にフィブリンのネットワークができてしまえば、線推素溶解現象が進むのが早いか、それとも線維芽細胞の侵入によってコラーゲン繊維網が形成されるのが早いかの競争となり、後者が勝ればその部に癒着組織が形成される。 Furthermore, in the thoracic cavity, intracranial, intrapericardial, intradural, etc., there is no major movement of the intestinal tract that begins 2 to 3 days after surgery. It is a competition between whether the elementary lysis phenomenon proceeds fast or whether the collagen fiber network is formed quickly by invasion of fibroblasts, and if the latter wins, an adhesion tissue is formed at that part.
本発明者は癒着組織の問題について攻究し、次のような知見を得た。
即ち、癒着が生じている部分では、組織修復部位の細胞から細胞成長因子などのサイトカインが多量に産生されていること、及び、癒着防止材料の内部に侵入したマクロファージなどの貪食細胞が多量のサイトカインを産生している。これらのサイトカインが局所に高濃度に貯留することによって周囲から組織修復を行う線維芽細胞などが活発に遊走、侵入し、それらの細胞が多量のコラーゲン線維を産生するため、急速に癒着組織が形成されることが判明した。従って、高濃度に貯留するサイトカインを、その部位から取り除き、健常な部分へ分散させ、更には創傷部位に侵入してくるマクロファージの活動を抑え、マクロファージが産生するサイトカインも健常部位に分散させる事が必要となる。そしてサイトカインの処理を行いつつ、癒着阻止材料を用いて創傷部位を保持し、周囲組織から遠ざけ、治癒を自然に行わせ創傷部位が完全に治癒させることで、癒着を防止できると考えるに至った。この機能を有する材料であれば、従来癒着防止が困難であった蠕動運動によるフィブリン網の破壊が期待できない部位の癒着も予防できる材料となりうると考え、上記知見を実現する手段を開発し本発明を完成させた。
The present inventor investigated the problem of the adhesion tissue and obtained the following knowledge.
That is, in the part where adhesion occurs, a large amount of cytokines such as cell growth factor is produced from cells at the tissue repair site, and phagocytic cells such as macrophages that have entered the adhesion prevention material contain a large amount of cytokines. Is producing. When these cytokines are stored locally at high concentrations, fibroblasts that repair tissues from the surrounding area actively migrate and invade, and these cells produce large amounts of collagen fibers, resulting in rapid formation of adhesion tissues. Turned out to be. Therefore, it is possible to remove cytokines stored at high concentration from the site and disperse them to a healthy part, further suppress the activity of macrophages entering the wound site, and disperse cytokines produced by macrophages to the healthy site. Necessary. And while treating the cytokine, the wound site was held using an adhesion prevention material, away from the surrounding tissue, and it came to be thought that adhesion can be prevented by healing naturally and allowing the wound site to heal completely . A material having this function is considered to be a material that can also prevent adhesion at a site where fibrin network destruction due to peristaltic movement, which has been difficult to prevent adhesion, can be prevented. Was completed.
本発明はいかなる組織、部位であっても確実に癒着を阻止できる医用材料を提供することを目的に開発されたものである。 The present invention was developed for the purpose of providing a medical material that can reliably prevent adhesion at any tissue or site.
本発明の要旨は生体親和性基材からなる構造物を骨格とし、そこに多価アルコールを４０重量％以上含むことを特徴とする癒着阻止用医用材料である。 The gist of the present invention is an adhesion-preventing medical material characterized in that a structure composed of a biocompatible substrate is used as a skeleton, and polyhydric alcohol is contained therein in an amount of 40% by weight or more.
即ち、損傷部において細胞が各種のサイトカインを産生するのは自然の働きであり、それを阻止することは不可能である。従ってこの問題を解決するには、本発明の生体内親和性基材からなる構造物より多価アルコールが基材周囲に放散し、それが水分と混和することによって、生体内親和性基材の周囲に一層の水分層が形成される。その水分層には周囲から細胞が侵入することが無く、また創傷部位に形成されたフィブリン網周囲に産生されたサイトカイン類の影響を受けることが無く、創傷部位で産生されたコラーゲンによる癒着を予防できるのである。当然、癒着阻止材料にも細胞が侵入することはない。 That is, it is natural for cells to produce various cytokines in the damaged part, and it is impossible to prevent them. Therefore, in order to solve this problem, polyhydric alcohol diffuses around the base material from the structure composed of the biocompatible base material of the present invention and mixes it with moisture, so that the biocompatible base material A single moisture layer is formed around the periphery. Prevents cells from invading into the moisture layer and is not affected by cytokines produced around the fibrin network formed at the wound site, preventing adhesion caused by collagen produced at the wound site It can be done. Naturally, cells do not enter the adhesion-preventing material.
本発明にかかる癒着阻止材料は創傷を受けた部位と周囲組織との間隙へ挿入し、癒着阻止材料が間隙に存在することで間隙がフィブリン網によって結びつくことを阻止し、創傷部と周囲組織間の癒着組織形成を抑える事ができる。具体的には本発明にかかる癒着阻止材料は特に腹腔内、胸腔内、頭蓋内、心嚢内等において、癒着を防ぎつつ組織修復を誘導する部位や、心筋内、血管内、肝臓内、眼球周囲、眼球内、鼻腔内、結合組織内、腱鞘内、硬膜内、脊髄腱内、気管内、気管枝内等において損傷を受けた壁面や組織内に穿った管腔壁面などの創傷治癒促進などにおいて好適に使用可能である。さらには従来の癒着防止材料では予防が困難であった蠕動運動の少ない組織等においても確実に癒着を予防することが可能となる。具体的には腹腔内でも腸の蠕動運動の少なくて癒着の生じやすい部位においても、また胸腔内や頭蓋内のような癒着の生じやすい部位においても癒着を阻止することが可能となる。
また癒着を防止した後も、膜等の形状が機能として必要な場合には生体内非吸収性物質を基材として使用し、癒着防止後に残留が問題になると予想される部位では、生体内吸収性物質を基材として用いると言うように、用途によって材料を選択することができる。
The adhesion-preventing material according to the present invention is inserted into the gap between the wounded site and the surrounding tissue, and the presence of the adhesion-preventing material in the gap prevents the gap from being bound by the fibrin network. Can suppress the formation of adhesion tissues. Specifically, the anti-adhesion material according to the present invention is a site that induces tissue repair while preventing adhesion, intramyocardial, intravascular, intrahepatic, and around the eyeball, particularly in the abdominal cavity, intrathoracic cavity, intracranial area, and pericardium. , Wound healing promotion in the eyeball, nasal cavity, connective tissue, tendon sheath, dura mater, spinal cord tendon, trachea, tracheal branch, etc. Can be suitably used. Furthermore, it is possible to reliably prevent adhesion even in tissues with little peristaltic movement, which has been difficult to prevent with conventional adhesion prevention materials. Specifically, it is possible to prevent adhesion even in the abdominal cavity even in a site where the intestinal peristaltic movement is small and adhesion is liable to occur, and also in a site where adhesion is liable to occur such as in the thoracic cavity or the cranium.
Even after prevention of adhesion, if the shape of the membrane or the like is required as a function, a non-absorbable substance in the body is used as a base material. The material can be selected depending on the application, such as using an active substance as a base material.
以下に本発明について詳細に説明する。
本発明で用いられる生体内親和性基材は、従来知られている埋植に用いられる材料を使用でき、さらには生体内非吸収性物質であっても、生体内吸収性物質のいずれも使用することができる。
The present invention is described in detail below.
The biocompatible substrate used in the present invention can use a conventionally known material used for implantation, and even a non-bioabsorbable substance or a bioabsorbable substance can be used. can do.
生体内非吸収性物質としては、合成高分子であるポリエステル、ポリウレタン、ポリアミド、シリコーン樹脂、フッ素含有樹脂等を用いることができる。
生体内分解吸収性物質としては天然由来高分子であるコラーゲン、セルロース、キチン、キトサン、多糖頬、カルボキシメチルセルロース（CMC）、澱粉、その分解生産物アミロース、アミロペクチン、デキストリン、合成アミロース等、合成高分子であるポリビニールアルコール、ポリエチレングリコール、ポリカブロラクトン、ポリ乳酸、ポリ酪酸、ポリグリコール酸、ポリカブロン酸、ポリアラキドン酸、ポリパラドキ酸、ポリメチレン・カーボネート及び、それらの誘導体等を用いることができる。
As the in vivo non-absorbable substance, synthetic polymers such as polyester, polyurethane, polyamide, silicone resin, fluorine-containing resin and the like can be used.
Biodegradable and absorbable substances such as natural polymers such as collagen, cellulose, chitin, chitosan, polysaccharide cheek, carboxymethylcellulose (CMC), starch, degradation products amylose, amylopectin, dextrin, synthetic amylose, etc. Polyvinyl alcohol, polyethylene glycol, polycabrolactone, polylactic acid, polybutyric acid, polyglycolic acid, polycabronic acid, polyarachidonic acid, polyparadoxy acid, polymethylene carbonate, derivatives thereof, and the like can be used.
これらの生体親和性基材の構造物は膜状、球状、紐状、棒状、板状、管状、方形状等使用目的、部位に適した形態とすることができる。形状については使用される部位によって異なり、これらの形状のうち目的を達成できる形状であれば、いずれの形状であっても用いることができる。
これら生体親和性基材構造物の厚みは10〜2000ミクロンが好ましく、この厚さより薄い場合には物理的障壁としての機能が不十分であり、この厚さ以上の場合には生体組織の機能維持に障害となる。
These biocompatible substrate structures can be in the form suitable for the intended use and site, such as a membrane, sphere, string, rod, plate, tube, square or the like. The shape varies depending on the site used, and any shape can be used as long as the shape can achieve the purpose.
The thickness of these biocompatible substrate structures is preferably 10 to 2000 microns, and if it is thinner than this thickness, the function as a physical barrier is insufficient, and if it exceeds this thickness, the function of living tissue is maintained. It becomes an obstacle.
生体親和性基材の構造物のうち、生体内非吸収性物質は癒着阻止が達成された後にも、その構造物の形状としての機能、物理強度等が求められる場合に用いられる。具体的には代用脳硬膜、代用心嚢膜等の用途が考えられる。
生体親和性物質の構造物のうち、生体内吸収性物質を用いる場合は、癒着阻止が達成された後に、その物質が残留することで問題を起こすと予想される場合、部位に使用される。予想される問題としては、構造物がいつまでも生体内に存在し続けた場合に、それを取り囲んで生体組織によるカプセルが形成され、そのカプセルが癒着の原因となりかねないため、ある程度の期間で消失する事が望ましい。
Among the biocompatible substrate structures, non-absorbable substances are used when the function as the shape of the structure, physical strength, etc. are required even after adhesion prevention is achieved. Specifically, applications such as a substitute brain dura mater and a substitute pericardium can be considered.
In the case of using a bioabsorbable substance among the biocompatible substance structures, it is used for a site when it is expected that the substance will remain after adhesion prevention is achieved. The anticipated problem is that if the structure continues to exist in the body forever, a capsule made of living tissue is formed surrounding it, and the capsule may cause adhesion, so it disappears in a certain period of time. Things are desirable.
本発明ではその期間を検討した結果、生体内における材料の形態維持日数（T）が3＜T＜30であることが望ましい。この期間より短い場合には、十分な癒着防止効果を得ることができないが、これは前にも述べた通りフィブリン網の形成、コラーゲン線維形成が開始される3日以上は形態の維持が必要である。反対にこれより長い場合には、カプセルを形成しやすくなる等、問題が発生する可能性があるために、形態が崩壊することが望ましい。
形態維持日数を調節するためには、生体内吸収性物質に架橋処理を行い生体内である程度の不溶化することが行われる。この不溶化によって、生体内において一定期間の形態維持を得て、その後、分解吸収される。そのような物性を与えるための架橋処理としては、グルタールアルデヒドやフォルムアルデヒド、ポリエポキシ化合物、ヘキサメテレンジイソシアネート等の化学架橋剤による処理、ガンマー線、電子線などの照射、加熱による熱架橋、繰り返しの凍結・融解による架橋等の物理的手段を用いてもよい。これらの架橋化処理は架橋剤が残存して細胞毒性を生じるといった不都合がなければ、如何なる架橋方法でも問題はない。
この架橋によって、本発明の癒着阻止用医用材料が３日以上、３０日以下の期間、その形態が維持させるよう、架橋の程度を調整することにより、癒着阻止を達成後、カプセル化等の問題を発生することなく、分解、吸収される癒着阻止用医療材料を得ることができる。
As a result of examining the period in the present invention, it is desirable that the number of days of maintaining the shape of the material (T) in the living body is 3 <T <30. If it is shorter than this period, it is not possible to obtain a sufficient anti-adhesion effect. However, as described above, it is necessary to maintain the form for more than 3 days when fibrin network formation and collagen fiber formation are started. is there. On the other hand, if the length is longer than this, problems such as easy formation of capsules may occur.
In order to adjust the number of days for maintaining the form, a cross-linking treatment is performed on the bioabsorbable substance to make it insoluble to some extent in the living body. By this insolubilization, shape maintenance for a certain period is obtained in the living body, and then it is decomposed and absorbed. As a crosslinking treatment for giving such physical properties, treatment with a chemical crosslinking agent such as glutaraldehyde, formaldehyde, polyepoxy compound, hexameterenediocyanate, irradiation with gamma rays, electron beam, etc., thermal crosslinking by heating, Physical means such as cross-linking by repeated freezing and thawing may be used. These crosslinking treatments have no problem with any crosslinking method as long as there is no inconvenience that the crosslinking agent remains to cause cytotoxicity.
By this cross-linking, the degree of cross-linking is adjusted so that the adhesion preventing medical material of the present invention maintains its form for a period of 3 days or more and 30 days or less. It is possible to obtain an adhesion-preventing medical material that is decomposed and absorbed without generating any of the above.
本発明の原理に沿って癒着を防止するには、基材が多価アルコールを４０重量％以上保有する必要がある。望ましくはさらに５０％以上、更に望ましくは６０％以上それらを保持することで効果を発揮する。
このように多量の多価アルコールが構造物より周囲に放散され構造物表面に存在することで、周囲から大量の水を流入し保持された状態となる。この時、周囲にインターロイキン、コロニー刺激因子等の各種サイトカインが存在する際には細胞遊走を誘発するが、これらが構造物周囲に形成された多量の水層によって、細胞の遊走を防ぐことができる。
In order to prevent adhesion in accordance with the principle of the present invention, the base material needs to hold 40% by weight or more of polyhydric alcohol. Desirably, the effect is exhibited by holding them at 50% or more, more desirably 60% or more.
In this way, a large amount of polyhydric alcohol is diffused from the structure to the surroundings and exists on the surface of the structure, so that a large amount of water flows from the surroundings and is held. At this time, cell migration is induced when various cytokines such as interleukin and colony-stimulating factor are present in the surroundings, but these can prevent cell migration by a large amount of water layer formed around the structure. it can.
使用される多価アルコールとしては、本発明の癒着阻止材料を埋植した際に、構造物の周囲に放散する多価アルコールであればいかなる多価アルコールも用いることができる。具体的にはポリエチレングリコール、メチルグリセロール、ポリオキシエレングリコシド、マルチトール、マンニトール、キシリトール、ソルビトール、ジプロピレングリコール、ブチレングリコール、バリン、プロピレングリコール、グリセロール、ポリグリセリン、グリセリン脂肪酸エステルの群から選ばれる少なくとも一つ以上であることが望ましいが、特にグリセロール、キシリトール、ソルビトール、低分子ポリエチレングリコールなど、医療分野や食品分野で使用されている多価アルコールが望ましい。 As the polyhydric alcohol to be used, any polyhydric alcohol can be used as long as it is a polyhydric alcohol that diffuses around the structure when the adhesion-preventing material of the present invention is implanted. Specifically, at least selected from the group of polyethylene glycol, methylglycerol, polyoxyelene glycoside, maltitol, mannitol, xylitol, sorbitol, dipropylene glycol, butylene glycol, valine, propylene glycol, glycerol, polyglycerin, glycerin fatty acid ester One or more is desirable, but polyhydric alcohols used in the medical field and food field such as glycerol, xylitol, sorbitol, and low molecular weight polyethylene glycol are particularly desirable.
構造物である生体親和性基材が疎水性の場合には、本発明の癒着阻止材料を埋植した際に、多価アルコールと共に構造物の周囲に放散する生体系保湿剤を用いることはできる。これは構造物周囲に水層形成の目的の他に、構造物に柔軟性を持たせることを目的としたものである。
用いることのできる生体系保湿剤としては、NMF（自然保湿因子）、アクアライサーEJ、プロヂュウ、混合異性化糖（ベンタバイテン）、アミノ酸、Ｌ−アスパラギン酸、L一アスパラギン酸ナトリウム、Dレアラニン、L−アルギニン、L−イソロイシン、塩酸リジン（L−リジン塩酸塩）、グリシン（アミノ酢酸）、L−グルタミン、L−グルタミン酸、L−グルタミン酸ナトリウム、ガンマーアミノ絡酸（ピペリジン）、L−スレオニン（L−トレオニン）、セリシン、セリン、レチロシン（L−チロジン）、L−トリプトファン、L−バリン、L−ヒスチジン塩酸塩、L−ヒドロキシプロリン（L一オキシプロリン）、フェニルアラニン、L−プロリン、L―口イシン、DL−ピロリドンカルボン酸（PCA）、DL−ピロリドンカルボン酸ナトリウム、乳酸、乳酸ナトリウム、尿素、尿酸、酸性ムコ多糖類、臍帯抽出液、鶏冠抽出液、ヒアルロン酸、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、グルクロン酸、グルクロン、コラーゲン、可溶性コラーゲン、コラーゲン加水分解物（ゼラチン）、アテロコラーゲン、エラスチン、水溶性エラスチン、細胞間脂質、スフィンゴ脂質（セラミド）、HSオイル、ケラチン、加水分解ケラチン、ケラチンアミノ酸、シスチン、L−メチオニン、シスチン、核酸、デオキシリボ核酸（DNA）、リボ核酸（RNA）、グアノシン、グアニン、リン酸、アデノシン3リン酸（ATP）、トリプトファンアデノシン、リン酸リボフラビンナトリウム、リン脂質、レシチン、大豆リン脂質（大豆レシチン）、大豆リゾリン脂質（リゾレシチン）、卵黄レシチン（卵黄リン脂質）、酵素、植物性複合酵素、蛋白分解酵素、脂肪分解酵素（リパーゼ）、のグループの中から選ばれた少なくとも一つ以上を含むものを用いることができる。
これら生体系保湿剤の含有量は種類によって異なり制限はないが、癒着阻止材料が柔軟性を持つ量が必要となる。
When the biocompatible substrate that is a structure is hydrophobic, it is possible to use a biological moisturizer that diffuses around the structure together with the polyhydric alcohol when the adhesion-preventing material of the present invention is implanted. . This is intended to give the structure flexibility in addition to the purpose of forming an aqueous layer around the structure.
Examples of biological moisturizers that can be used include NMF (natural moisturizing factor), Aqualyser EJ, Produ, mixed isomerized sugar (Bentabaiten), amino acids, L-aspartic acid, sodium L-aspartate, D-realanine, L -Arginine, L-isoleucine, lysine hydrochloride (L-lysine hydrochloride), glycine (aminoacetic acid), L-glutamine, L-glutamic acid, sodium L-glutamate, gamma-amino tangle acid (piperidine), L-threonine (L- Threonine), sericin, serine, retyrosine (L-tyrosine), L-tryptophan, L-valine, L-histidine hydrochloride, L-hydroxyproline (L monooxyproline), phenylalanine, L-proline, L-mouth isine, DL-pyrrolidonecarboxylic acid (PCA), DL-pyrrolidonecarboxylate sodium, lactic acid, sodium lactate , Urea, uric acid, acidic mucopolysaccharide, umbilical cord extract, chicken crown extract, hyaluronic acid, sodium hyaluronate, sodium chondroitin sulfate, glucuronic acid, glucuron, collagen, soluble collagen, collagen hydrolyzate (gelatin), atelocollagen, Elastin, water-soluble elastin, intercellular lipid, sphingolipid (ceramide), HS oil, keratin, hydrolyzed keratin, keratin amino acid, cystine, L-methionine, cystine, nucleic acid, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), Guanosine, guanine, phosphate, adenosine triphosphate (ATP), tryptophan adenosine, riboflavin sodium phosphate, phospholipid, lecithin, soybean phospholipid (soy lecithin), soybean lysophospholipid (lysolecithin), egg yolk lecithin (egg yolk phospholipid) , Fermentation , Can be used include plant-derived composite enzyme, proteolytic enzyme, lipolytic enzyme (lipase), at least one or more selected from the group of.
The content of these biological moisturizing agents varies depending on the type and is not limited, but an amount by which the adhesion prevention material is flexible is required.
本発明にかかる癒着阻止材料に用いられる多価アルコール、生体系保湿剤は構造物内部で化学的や物埋的な手段で固定化されている必要はなく、ただ単に含有されていれば良い。このようにして多量の多価アルコールや生体系保湿成分を含有した場合、その構造物は周囲から持続的に水を吸収し始めると同時に、多価アルコールや生体系保湿成分は癒着阻止材料の外に出始めて、材料の外部においても水を抱え込み、癒着防止の効果をもたらす。
また本発明の癒着阻止材料の形状は、適応する部位に最適な形状にして用いられる。具体的には膜状、球状、紐状、棒状、板状、管状、方形状等のいずれかの形態とすることができる。また、適用方法としてスプレーの様に噴霧する方法も可能である。具体的には本発明の癒着阻止材料を微細な粉体とし、それを加圧状態の容器より噴霧させる、あるいは粉体となった生体親和性基材からなる構造物とアルコールが、噴霧時に一体となるようにすること等の方法によって可能となる。
The polyhydric alcohol and biological humectant used in the adhesion-preventing material according to the present invention do not need to be fixed by chemical or embedded means inside the structure, but may simply be contained. When a large amount of polyhydric alcohol or biological moisturizing component is contained in this manner, the structure starts to absorb water continuously from the surroundings, and at the same time, the polyhydric alcohol or biological moisturizing component is not included in the adhesion prevention material. It begins to come out, and also holds water outside the material, bringing about the effect of preventing adhesion.
The shape of the adhesion-preventing material of the present invention is used in an optimum shape for the applicable site. Specifically, it can be in any form such as a film shape, a spherical shape, a string shape, a rod shape, a plate shape, a tubular shape, and a rectangular shape. Moreover, the method of spraying like a spray is also possible as an application method. Specifically, the adhesion-preventing material of the present invention is made into a fine powder and sprayed from a pressurized container, or a structure composed of a biocompatible substrate in a powder and alcohol are integrated during spraying. This can be achieved by a method such as
膜状物は癒着を要望したい組織の間に挿入し用いられ、大きさ、形は使用時に調整される。球状物、方状物については、癒着阻止が望まれる欠損部に充填し用いられ、充填に必要な量が用いられる。紐状物は、例えば癒着阻止が望まれる筒状部位の周囲に巻き付けて用いることができる。棒状物は、例えば癒着阻止が望まれる腔、瘻等に挿入して用いることができる。板状物は膜状と類似の用い方がなされるが、膜状と違い柔軟性を持たない形状である。管状物は、例えばドレナージ用チューブ等の管状で周囲との癒着を阻止したい場合に用いられる。 The membranous material is inserted and used between tissues where adhesion is desired, and the size and shape are adjusted at the time of use. For the spherical and rectangular objects, a defect portion where adhesion prevention is desired is filled and used, and an amount necessary for filling is used. The string-like object can be used, for example, by being wound around a cylindrical part where adhesion prevention is desired. The rod-shaped object can be used by being inserted into a cavity, heel or the like where adhesion prevention is desired, for example. The plate-like material is used in a manner similar to the film shape, but has a shape that does not have flexibility unlike the film shape. Tubular objects are used when it is desired to prevent adhesion with the surroundings, such as a drainage tube.
本発明の膜状物等各種形状について、多価アルコールを含む生体親和性膜状物の一方の面に、多価アルコールを透過することの無い膜状物を組み合わせ癒着阻止材料とすることもできる。
本発明の癒着阻止用医用材料は癒着防止の他に、血栓付着防止、細胞の付着防止の機能も持ち、腹腔内、胸腔内、頭蓋内、心嚢内、心室内、心筋内、血管内、肝臓内、眼球周囲、眼球内、涙管内、鼻腔内、結合組織内、腱鞘内、硬膜内、脊髄腔内、気管内、気管枝内、の何れかの部位において使用することができる。
Regarding various shapes such as the film-like material of the present invention, a film-like material that does not permeate polyhydric alcohol can be combined with one surface of a biocompatible film-like material containing polyhydric alcohol to form an adhesion prevention material. .
In addition to preventing adhesions, the medical material for preventing adhesion of the present invention also has functions of preventing thrombus adhesion and cell adhesion, and includes intraperitoneal, intrathoracic, intracranial, intrapericardial, intraventricular, intramyocardial, intravascular, and liver. It can be used at any of the following sites: intraocular, periocular, intraocular, intra lacrimal, intranasal, connective tissue, intratendon sheath, intradural, intrathecal, intratracheal, intratracheal branch.
本発明にかかる医用材料の製造方法においては、生体内親和性基材で、膜状、球状、紐状、棒状、板状、管腱状、方形状等の構造物に成型した後に多価アルコールを含有付着させる。生体内親和性基材が生体内吸収性物質である場合、構造物とした後に不溶化処理を行い、その後に多価アルコール、及び／又は、生体系保湿成分を含有付着させる。
更に生体内親和性基材が水に溶解できる物質である場合、膜状、球状、紐状、棒状、板状、管腔状、方形状等の構造物に成型する際に、水溶液とした基材の物質を所望の形状の型に入れた後に、それを凍結乾燥することによってスポンジ状の構造物を作ることができる。乾燥後それを不溶化し、その後スポンジ状構造物に再び液状物を流し込ませた後に乾燥させる製造することができる。
In the method for producing a medical material according to the present invention, a polyhydric alcohol after being formed into a structure having a biocompatible base material, such as a film shape, a spherical shape, a string shape, a rod shape, a plate shape, a tube tendon shape, or a square shape. Containing. In the case where the biocompatible substrate is a bioabsorbable substance, an insolubilization treatment is performed after forming the structure, and then a polyhydric alcohol and / or a biological moisturizing component is contained and adhered.
In addition, when the biocompatible substrate is a substance that can be dissolved in water, the aqueous solution is used as a base when forming into a membrane, sphere, string, rod, plate, lumen, square or other structure. A sponge-like structure can be made by placing the material of the material into a mold of the desired shape and then freeze-drying it. It can be manufactured by insolubilizing it after drying and then pouring the liquid material again into the sponge-like structure and then drying it.
このような材料を製造する過程においては、多価アルコール、及び／又は、生体系保湿成分を保有させる際に、不溶化後に、まずは含水により構造物を膨潤させ、その後に多価アルコール、及び／又は、生体系保湿成分を保有する液体に構造物を触れさせ、水と多価アルコール、及び／又は、生体系保湿成分とを置換させて、構造物内に多量の多価アルコール、及び／又は、生体系保湿成分を残す、という順序を、製造過程の少なくとも一部に持つ事が好ましい。
以下、本発明の実施例を示すが、本発明はこれら実施例により制限されるものではない。
In the process of producing such a material, when the polyhydric alcohol and / or biological system moisturizing component is retained, after insolubilization, the structure is first swollen with water, and then the polyhydric alcohol and / or , By bringing the structure into contact with the liquid containing the biological moisturizing component and replacing water and the polyhydric alcohol and / or the biological moisturizing component, a large amount of the polyhydric alcohol in the structure, and / or It is preferable that at least a part of the manufacturing process has an order of leaving the biological moisturizing component.
Examples of the present invention will be described below, but the present invention is not limited to these examples.
実施例１
平均分子量が約10万未満のカルボキシメチルセルロース（CMC）を用いて、癒着阻止用膜のテストサンプルを作成した。まず、このCMCを塩酸によってpH3.5として、重量濃度2.5％の溶液を作り、この溶液をテフロンシャーレの中に流して凍結乾燥させスポンジを作成した。作成後、120℃で12時間、減圧しつつ加熱して空気に曝さないように配慮し、熱架橋を導入したスポンジの板を作成した。
つぎにそのスポンジ板に、先ほど使用したCMC液を更に重層的に注いで、スポンジ内を充満させた。これを自然乾燥させて、CMCの膜を作成し、更に120℃で12時間、減圧して空気に曝さないように配慮して熱架橋を行い、CMCの熱架橋膜を作成した。このときの膜の乾燥重量を測定しておいた。
作成した膜を蒸留水の中で一昼夜洗浄して、酸性を中和、洗浄後、この膜を10%のグリセロールに浸漬させ、水とグリセロールを置換させた。この処置によって、厚み0.1mm、で大きさ6cm×12cmの膜を作成した。このときの重量を測定し、乾燥重量との対比によってこの膜の中に含まれるグリセロールの重量％を算出した結果、約70重量%であった。作成した膜は紫外線照射によって滅菌した。
Example 1
A test sample of an adhesion-preventing membrane was prepared using carboxymethylcellulose (CMC) having an average molecular weight of less than about 100,000. First, the CMC was adjusted to pH 3.5 with hydrochloric acid to prepare a solution having a weight concentration of 2.5%, and this solution was poured into a Teflon petri dish and freeze-dried to prepare a sponge. After the preparation, a sponge board into which thermal crosslinking was introduced was prepared by taking care not to be exposed to air by heating at 120 ° C. while reducing pressure for 12 hours.
Next, the CMC solution used earlier was poured into the sponge plate in a multilayered manner to fill the sponge. This was air-dried to form a CMC film, and further subjected to thermal crosslinking under reduced pressure at 120 ° C. for 12 hours so as not to be exposed to air, thereby preparing a CMC thermal crosslinked film. The dry weight of the film at this time was measured.
The prepared membrane was washed in distilled water all day and night to neutralize the acidity. After washing, the membrane was immersed in 10% glycerol to replace water and glycerol. By this treatment, a film having a thickness of 0.1 mm and a size of 6 cm × 12 cm was formed. The weight at this time was measured, and the weight percent of glycerol contained in the membrane was calculated by comparison with the dry weight. As a result, it was about 70 weight percent. The prepared membrane was sterilized by ultraviolet irradiation.
実施例２
実施例１で作成した、グリセロールを浸漬させる前の膜に、常温で固形のキシリトールを浸漬させた。
キシリトールの粉未を水に溶解し、その水溶液を調製した。その中に乾燥した膜を浸漬させることによって、膜が水で膨潤し、その後にキシリトールを染み込増すことが可能であった。何回か浸漬させた後に乾燥させることによって、40％以上のキシリトールをしみ込ませた膜を作成した。
Example 2
Solid xylitol at room temperature was immersed in the membrane prepared in Example 1 before immersing glycerol.
The powder of xylitol was dissolved in water to prepare an aqueous solution thereof. By immersing the dried film in it, it was possible to swell the film with water and then soak up xylitol. A film soaked with 40% or more of xylitol was prepared by dipping several times and then drying.
実施例３
実施例２において、キシリトールの代わりにソルビトールを用いることで、同様に40％以上のソルビトールをしみ込ませた膜を作成した。
Example 3
In Example 2, a film soaked with 40% or more of sorbitol was similarly prepared by using sorbitol instead of xylitol.
実施例４
実施例２において、キシリトールの代わりに分子量300のポリエチレングリコールを用いることで、同様に40％以上のポリエチレングリコールをしみ込ませた膜を作成した。
実施例５
平均分子量10万のCMCを塩酸酸性によってpH3.5にして、重量濃度2.5%の溶液を作った。
次にその溶液をテフロンシャーレの中に流して凍結乾燥させ、その後に、120℃で12時間、減圧し加熱して空気に曝さないように配慮し、熱架橋を行って、不溶化されたフィルムを作成した。
つぎにそのフィルムに、先ほど使用したCMC液を更に重層的に注いだ後、それを自然乾燥させて、CMCの膜を作成し、更に120℃で12時間、減圧して空気に曝さないように配慮して熱架橋を行い、CMCの熱架橋膜を作成した。
できた不溶性の膜を蒸留水の中で一昼夜洗浄して、塩酸を洗浄し酸性を中和した。
つぎに洗浄した膜を100%のグリセリン液に一昼夜浸漬させて、水とグリセロールを置換させた。この処置によって、厚み0．1mm、広さ6cm×１2cmの膜を作成した。この膜の中に含まれるグリセリンの量は、約90重量％であった。
このようにして作成した膜を紫外線照射によって滅菌した。
Example 4
In Example 2, by using polyethylene glycol having a molecular weight of 300 instead of xylitol, a membrane soaked with 40% or more of polyethylene glycol was similarly prepared.
Example 5
A CMC having an average molecular weight of 100,000 was adjusted to pH 3.5 with hydrochloric acid acid to prepare a solution having a weight concentration of 2.5%.
Next, the solution was poured into a Teflon petri dish and freeze-dried, and after that, under reduced pressure at 120 ° C. for 12 hours, care was taken so as not to be exposed to the air by thermal crosslinking. Created.
Next, after the CMC liquid used previously is poured into the film in a multi-layered manner, it is naturally dried to create a CMC film, which is further depressurized at 120 ° C for 12 hours so as not to be exposed to air. Taking into account thermal crosslinking, a CMC thermal crosslinked film was prepared.
The resulting insoluble membrane was washed in distilled water for a whole day and night, and hydrochloric acid was washed to neutralize the acidity.
Next, the washed membrane was immersed in a 100% glycerin solution for one day to replace water and glycerol. By this treatment, a film having a thickness of 0.1 mm and a width of 6 cm × 12 cm was formed. The amount of glycerin contained in this membrane was about 90% by weight.
The membrane thus prepared was sterilized by ultraviolet irradiation.
実施例６
実施例４においてグリセロールを保有させるプロセスの時間を調整することによって、グリセロールの含量を変えた膜を作成した。その結果、グリセロールの含有量が20%、25％、30%、35％、40%、45％、50%、60％、70％の膜を作ることができた。
なお、グリセロールの定量は、液クロマトグラフィー法によっても行った。液クロマトグラフィー法は作成したグリセロール保有の膜からグリセロールを水で溶出し、その溶出液の中に含まれるグリセロールの量を液クロマトグラフィーで測定した。液体クロマトグラフィー（島津製作所）にカラム（昭和電工社製ShodexのSB802．5HQ）を用いてグリセロール量の定量を行った。
Example 6
Membranes with varying glycerol content were prepared by adjusting the time of the process of retaining glycerol in Example 4. As a result, films with glycerol content of 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, and 70% could be made.
Glycerol was also quantified by liquid chromatography. In the liquid chromatography method, glycerol was eluted from the prepared glycerol-containing membrane with water, and the amount of glycerol contained in the eluate was measured by liquid chromatography. The amount of glycerol was quantified using a column (Shodex SB802.5HQ manufactured by Showa Denko KK) in liquid chromatography (Shimadzu Corporation).
試験例１
癒着阻止の試験はJames W. Burns, M. Jude Colt, Laurette S. Burgess, Kevin C. Skinner: Preclinical Evaluation of SeprafilmTM Bioresorble Membrane．Eur J Surg, 163: Supple 577：40-48, 1997 及び James W. Burns, Laurett Burgess, Kevin Skinner, Rosalind Rose, M. Jude Colt, Michael P Diamond: A hyaluronate based gel for the prevention of postsurgical adhesion: evaluation in two aninal species. Fertility and Sterility 66: 5: 814−821, 1996．方法に準じて行った。
Test example 1
The adhesion prevention test was performed by James W. Burns, M. Jude Colt, Laurette S. Burgess, Kevin C. Skinner: Preclinical Evaluation of Seprafilm ™ Bioresorble Membrane. Eur J Surg, 163: Supple 577: 40-48, 1997 and James W. Burns, Laurett Burgess, Kevin Skinner, Rosalind Rose, M. Jude Colt, Michael P Diamond: A hyaluronate based gel for the prevention of postsurgical adhesion: evaluation in two aninal species. Fertility and Sterility 66: 5: 814-821, 1996. It carried out according to the method.
実施例1で作成した膜を、それぞれを3試料ずつラットの腹腔内に挿入し、腹壁と盲腸部分を擦過して傷を付けて、14日目に採取して、周囲との癒着と細胞の侵入を検査したところ、全ての例で癒着は認められなかった。 Membranes prepared in Example 1 were inserted into the abdominal cavity of 3 samples each, and the abdominal wall and cecum were scratched and scratched. When examined for intrusion, no adhesions were observed in all cases.
試験例２
胸部領域での抗癒着効果を観察する目的で、次の実験を行った。
ビーグル犬を全身麻酔下に気管内チューブを挿入して人工呼吸を施した後、左の第6肋間を開いて、肺を露出し、肺組織表面を自然乾燥させて肺表面の細胞に障害を与えた後に実施例5で作成した材料を肺組織と胸壁との間に置いて、術後の癒着状況を観察した。
Test example 2
In order to observe the anti-adhesion effect in the chest region, the following experiment was conducted.
The beagle dog was inserted into the endotracheal tube under general anesthesia and artificially ventilated, and then the left sixth intercostal space was opened to expose the lungs, and the lung tissue surface was naturally dried to damage the cells on the lung surface. After application, the material prepared in Example 5 was placed between the lung tissue and the chest wall, and the postoperative adhesion situation was observed.
材料を6cm×１2cmの長方形として使用した。膜の厚さは約0.1mmであった。使用した動物は一つの試料につき３匹ずつであった。 The material was used as a 6 cm × 12 cm rectangle. The film thickness was about 0.1 mm. Three animals were used per sample.
術後２週間経過して、再び動物に全身麻酔をかけて、今度は第９肋間を開いて、前回手術の第6肋間の胸腔壁の手術創と肺組織との間の癒着状況を観察した。 Two weeks after the operation, the animals were given general anesthesia again, this time the 9th intercostal space was opened, and the adhesion between the surgical wound on the chest wall and the lung tissue between the 6th intercostal space of the previous operation was observed. .
このようにして胸部領域での癒着状態を観察してみると、40%、45%、50%、60％、70%のグリセリンの保有率を持つ膜では、全ての例で、癒着は見られなかったが、20%、30％、35％の膜ではそれぞれ3匹のうちで1匹ずつ肺組織の一部が胸壁に付着していた。使用した膜は全ての例で消失しており、その部位には存在していなかった。 In this way, when the adhesion state in the thoracic region is observed, adhesion is seen in all cases in the membranes having a glycerin retention rate of 40%, 45%, 50%, 60%, 70%. In the 20%, 30%, and 35% membranes, one out of three each had some lung tissue attached to the chest wall. The membrane used disappeared in all cases and was not present at that site.
光学顕微鏡による組織切片のへマトキシリン染色拭料の観察では、癒着していない部位では手術創部分は完全に修復され、その表面は連続した漿膜細胞、つまり中皮細胞の層が覆っていた20%、30%、35％のグリセロール保有の膜の癒着部分では、肺組織と胸壁との間は線維性の組織で結ばれ、線維芽細胞と毛細血管が多くみとめられた。 In the observation of the hematoxylin-stained wipe on the tissue section with an optical microscope, the surgical wound was completely repaired at the unadhered site, and the surface was covered with a continuous serosal cell, that is, a layer of mesothelial cells, 20%, In the adhesion part of the membranes containing 30% and 35% glycerol, fibrous tissue was connected between the lung tissue and the chest wall, and many fibroblasts and capillaries were observed.
この実験の結果、グリセロールが少しでも保有されていると腹部領域では確実に癒着を防ぐことが明らかとなったが、胸部領域ではグリセリンの保有量が少なくとも40%以上保有していなければ、胸部領域では癒着を完全に阻止できない事が判明した。 As a result of this experiment, it was found that adhesion of glycerol in the abdominal region surely prevented adhesion even if a little glycerol was retained, but in the chest region, if the glycerin retention amount is not at least 40% or more, Then it turned out that adhesion cannot be completely prevented.
試験例３
実施例2、3及び4で作成した、キシリトール、ソルビトール及び分子量300のポリエチレングリコールを含有する材料を用いて、試験例2と同じ試験を行ったところ、グリセロールとほぼ同じく、40％以上保有していれば、腹部領域と胸部領域で抗癒着効果を発揮する結果を得た。
Test example 3
Using the material containing xylitol, sorbitol and polyethylene glycol having a molecular weight of 300, prepared in Examples 2, 3 and 4, the same test as in Test Example 2 was carried out. As a result, an anti-adhesion effect was obtained in the abdominal region and the chest region.
比較例1
動物実験として、イヌを全身麻酔下に清潔操作で第6肋間を開いて肺を露出した。このとき、肺組織を1時間空気に曝して、肺表面の細胞に障害を与えて、その後に胸を閉じた。
胸を閉じるに当たって、3頭のイヌでは実施例１で作成した膜を傷の直下で、肺と胸腔壁との間に置いて閉胸した。また3頭のイヌでは、対照として市販のセブラフイルムを同様に傷の直下に置いた。真に対象の実験としては、3頭のイヌでは、それらの膜を置くことなく単純に閉胸した。
なお対照品として使用した市販のセブラフイルムは、ヒアルロン酸、CMC、をEDC（トエチルー3（3−ジメチルアミノプロピル）カルボジイミド）により架橋された膜であって、グリセロールは保有されていない。
Comparative Example 1
As an animal experiment, the dog was opened under a general anesthesia and the 6th intercostal space was opened to expose the lungs. At this time, the lung tissue was exposed to air for 1 hour to damage the cells on the lung surface, and then the chest was closed.
In closing the chest, the three dogs closed the chest by placing the membrane prepared in Example 1 directly under the wound and between the lung and the chest wall. In addition, in 3 dogs, a commercially available sebra film was placed directly under the wound as a control. In a true subject experiment, three dogs simply closed their chests without placing their membranes.
The commercially available cebrafilm used as a control product is a membrane in which hyaluronic acid, CMC, is crosslinked with EDC (toethyl-3- (3-dimethylaminopropyl) carbodiimide), and does not contain glycerol.
手術後2週間経過して動物を全身麻酔にかけて、第8肋間から開胸して、傷への肺組織の癒着状況を観察した結果、作成した膜を使用した例は3頭とも全く肺組織の癒着は見られなかった。これに対して、セブラフイルムを使用した例の3頭と、膜を使用しなかった例の3頭では、全ての例において肺組織の胸腔壁への全面的な癒着が見られた。そしてその癒着組織は、鈍的に剥がすことは不可能であり、剪刀によって剥がしたが、この剥離作業によって肺組織の一部に欠損が生じた。すなわち、癒着によって、再手術時には肺組織を傷害する恐れのあることが示された。 Two weeks after the operation, the animals were subjected to general anesthesia, the thoracotomy was performed from the 8th intercostal space, and the adhesion of the lung tissue to the wound was observed. There was no adhesion. On the other hand, in the three animals using the sebra film and the three animals not using the membrane, in all cases, complete adhesion to the chest cavity wall of the lung tissue was observed. The adhesion tissue could not be peeled off bluntly and was peeled off with a scissors, but this peeling operation caused a defect in part of the lung tissue. That is, it was shown that adhesion may damage lung tissue during reoperation.
比較例２
心膜における癒着防止が可能かどうかの検討を行った。
前述したイヌの実験と同じように、動物を全身麻酔下で清潔操作のもとで左第8肋間から開胸し、肺組織をガーゼでくるみ下方に押しやり、心臓を取り囲む心膜を露出した。
次に心膜を切開した後に、心臓を露出し、1時間空気に曝した後に、心臓表面を軽くガーゼで擦過し、表面に障害を与えた。そして心膜を元通りに縫合し、肺組織をさらに元の位置に戻して閉胸し、手術を終わった。
この心膜縫合に際して、膜を閉じる前に、実施例１で作成したCMC膜の6cm平方を心臓と心膜との間に挿入して膜を閉じる実験を3頭のイヌにおいて行った。また、同様に3頭のイヌにおいてはセブラフイルムを同じサイズに切ってその場に置いた。また3頭のイヌにおいては膜を置くことなく心膜の切開部を閉じた。
手術後2週間経過してイヌを全身麻酔下に開胸し、心膜部分を観察したところ、作成したCMC膜では全く癒着は認められなかった。これに対して、セブラフイルム群と膜を使用しなかった群では、全ての例において、心膜と心臓とが癒着していた。
これらの癒着例では、その癒着を剥離するためには、鈍的な手法では剥離することができなかったために、一部は剪刀をもちいて剥離したが、この時心臓組織の一部を損傷した。すなわち心臓手術にて再手術を行う必要があれば、前回の手術によって心膜と心臓との間で癒着がおきていることから、それを剥離するための操作において心臓組織を傷害する恐れのあることを示している。
Comparative Example 2
We examined whether adhesion in the pericardium could be prevented.
As in the dog experiment described above, the animal was opened from the left eighth intercostal space under clean anesthesia under general anesthesia, and the lung tissue was pushed down with a gauze to expose the pericardium surrounding the heart. .
Next, after incising the pericardium, the heart was exposed and exposed to air for 1 hour, and then the surface of the heart was gently abraded with gauze to damage the surface. The pericardium was sutured again, the lung tissue was returned to its original position, the chest was closed, and the operation was completed.
In this pericardial suture, before closing the membrane, an experiment was conducted in three dogs in which 6 cm square of the CMC membrane prepared in Example 1 was inserted between the heart and pericardium to close the membrane. Similarly, in three dogs, the serafilm was cut into the same size and placed on the spot. In three dogs, the pericardial incision was closed without placing the membrane.
Two weeks after the operation, the dog was opened under general anesthesia, and the pericardium was observed. No adhesion was observed on the prepared CMC membrane. In contrast, in all cases, the pericardium and the heart were adhered in the sebra film group and the group that did not use the membrane.
In these adhesion cases, in order to remove the adhesion, it was not possible to remove it with a blunt technique, so a part was removed using a scissors, but at this time a part of the heart tissue was damaged . In other words, if it is necessary to re-operate during cardiac surgery, the adhesion between the pericardium and the heart has been caused by the previous surgery, which may damage the heart tissue in the operation to remove it. It is shown that.
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